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1.
Mol Pharm ; 19(2): 520-531, 2022 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-34936359

RESUMO

Mucus represents a strong barrier to tackle for oral or pulmonary administered drugs, especially in mucus-related disorders. This study uses a pathological cystic fibrosis (CF) mucus model to investigate how mucus impacts the passive diffusion of 45 ad hoc commercial drugs selected to maximize physicochemical variability. An in vitro mucosal surface was recreated by coupling the mucus model to a 96-well permeable support precoated with structured layers of phospholipids (parallel artificial membrane permeability assay, PAMPA). Results show that the mucus model was not a mere physical barrier but it behaves like an interactive filter. In nearly one-half of the investigated compounds, the diffusion was reduced by mucus, while other drugs were not sensitive to the mucus barriers. We also found that permeability can be enhanced when drug-calcium salts are formed. This was confirmed with cystic fibrosis sputum as a rough ex vivo model of CF mucus. Since the drug discovery process is characterized by a high rate of failure, the mucus platform is expected to provide an efficient support to early reduce the number of poor-performing drug candidates.


Assuntos
Fibrose Cística , Fibrose Cística/tratamento farmacológico , Difusão , Humanos , Muco , Permeabilidade , Escarro
3.
Phys Rev Lett ; 129(3): 038101, 2022 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-35905353

RESUMO

Myriads of cilia beat on ciliated epithelia, which are ubiquitous in life. When ciliary beats are synchronized, metachronal waves emerge, whose direction of propagation depends on the living system in an unexplained way. We show on a reconstructed human bronchial epithelium in vitro that the direction of propagation is determined by the ability of mucus to be transported at the epithelial surface. Numerical simulations show that longitudinal waves maximize the transport of mucus while transverse waves, observed when the mucus is rigid and still, minimize the energy dissipated by the cilia.


Assuntos
Brônquios , Cílios , Epitélio , Humanos , Muco
4.
Molecules ; 27(14)2022 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-35889482

RESUMO

In this study, mucoactive self-emulsifying drug delivery systems (SEDDSs) based on sustained release of N-acetylcysteine (NAC) were developed for providing effective intestinal mucopermeation. Polymeric ionic complexes of NAC were formed with polyethyleneimine (PEI), Eudragit E 100, and Eudragit RS 100 and loaded into a novel SEDDS. The SEDDSs exhibited a stable average size of 75 ± 12 nm (polydispersity index (PDI) < 0.3) and showed a rise in the zeta potential from -17.31 mV to -7.72 mV. On Caco-2 cells, SEDDSs at 1-3% were non-cytotoxic. An average of 91.8 ± 5.4% NAC was released from SEDDSs containing Eudragit E 100 (p ≤ 0.05) and Eudragit RS 100 (p ≤ 0.001) complexes at a significantly slower rate within 80 min, whereas the SEDDS containing PEI released NAC in a matter of seconds. Similarly, the SEDDS complexes revealed a time-dependent reduction in mucus dynamic viscosity of 52.6 ± 19.9%. Consequently, as compared with a blank SEDDS, mucodiffusion revealed about 2- and 1.8-fold significantly greater mucopermeation of SEDDSs anchoring Eudragit E 100-NAC and RS 100-NAC complexes (p ≤ 0.05), respectively. The mucoactive SEDDSs, which steadily released NAC while permeating the mucus, were linked to a significantly increased mucopermeation in vitro as a result of optimal mucolytic targeting.


Assuntos
Emulsificantes , Expectorantes , Células CACO-2 , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Emulsões , Humanos , Muco , Permeabilidade , Compostos de Sulfidrila
5.
Front Immunol ; 13: 865273, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35799795

RESUMO

Objective: Inflammatory bowel disease (IBD) often occurs along with extraintestinal manifestations, including hepatic injury. Milk fat globule membrane (MFGM) is an active substance with a potential anti-inflammation activity. However, its alleviated effect and mechanisms in IBD as well as the IBD-induced secondary liver injury are still unclear. Methods: C57BL/6J mice were administered with a 21-day oral gavage of MFGM, followed by 7 days of drinking water with 4% dextran sulfate sodium (DSS). Disease activity index (DAI), histological features, and cytokines of the colon and liver were evaluated. Then, RNA-seq of the colon and liver was conducted. The gut microbiota was assessed by analyzing 16S rRNA gene sequences, and finally the integrity and the function of the mucus barrier were evaluated by Alcian blue staining, real-time quantitative PCR, and ELISA. Results: Prophylactic MFGM treatment was effective against colitis to include effects in body weight loss, DAI score, colonic length, intestinal pathology, and histological score. Additionally, prophylactic MFGM decreased the levels of interleukin (IL)-1ß, IL-6, and myeloperoxidase in colonic tissue, while it increased the IL-10 level. Moreover, the gene expressions of MUC2, MUC4, Reg3b, and Reg3g associated with the production of the molecular mediator of immune response, membrane invagination, and response to protozoan were strikingly upregulated when administered with MFGM. On the other hand, the beneficial effects of MFGM were related to the enriched abundance of genera such as Faccalibacumum and Roseburia in feces samples. Consistently, the administration of MFGM was also found to alleviate DSS-induced hepatic injury. Furthermore, the glutathione transferase activity pathway was enriched in the liver of MFGM-treated mice after DSS administration. Mechanistically, prophylactic MFGM enhanced the mucosal barrier by increasing the gene levels of Reg3b and Reg3g. Meanwhile, the alleviation of MFGM on liver injury was dependent on the reduced hepatic oxidative stress. Conclusions: MFGM attenuated colitis and hepatic injury by maintaining the mucosal barrier and bacterial community while inhibiting oxidative stress, which might be an effective therapy of hepatic injury secondary to IBD.


Assuntos
Colite , Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Animais , Colite/patologia , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , Glicolipídeos , Glicoproteínas , Doenças Inflamatórias Intestinais/metabolismo , Mucosa Intestinal/metabolismo , Gotículas Lipídicas , Fígado/patologia , Camundongos , Camundongos Endogâmicos C57BL , Muco , RNA Ribossômico 16S/genética
6.
Front Cell Infect Microbiol ; 12: 856962, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35774401

RESUMO

The mucosal surfaces that form the boundary between the external environment and the underlying tissue are protected by a mucus barrier. Mucin glycoproteins, both secreted and cell surface mucins, are the major components of the barrier. They can exclude pathogens and toxins while hosting the commensal bacteria. In this review, we highlight the dynamic function of the mucins and mucus during infection, how this mucosal barrier is regulated, and how pathogens have evolved mechanisms to evade this defence system.


Assuntos
Mucinas , Muco , Bactérias/metabolismo , Glicoproteínas/metabolismo , Mucinas/metabolismo , Membrana Mucosa/microbiologia , Muco/metabolismo
7.
J Agric Food Chem ; 70(28): 8776-8787, 2022 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-35802804

RESUMO

Previous studies have found that soybean protein, especially soybean 7S protein (ß-conglycinin), exhibits digestion resistance, but the mechanism of digestion resistance and its implications for human health are still unclear. Here, we show that the extracted soybean 7S protein contains both oligomer globulins and amyloid aggregates, while the gastric digested soybean 7S protein only contains amyloid aggregates and thus exhibits digestion resistance. An animal experiment shows that un-digestible soybean 7S protein effectively prevents aspirin-induced acute gastric mucosa damage. The impacts of un-digestible soybean 7S protein on gastric mucus barrier properties are investigated using quartz crystal microbalance with dissipation (QCM-D), Langmuir monolayer, and multiple particle tracking (MPT). Results show that these un-digestible protein aggregates can penetrate into gastric mucus, increase the viscosity and compactness of the mucin layer, and reinforce the gastric mucus barrier properties. The findings are helpful to understand that high consumption of non-fermented soybean foods is associated with a decreased risk of gastric cancer.


Assuntos
Mucosa Gástrica , Globulinas , Proteínas de Armazenamento de Sementes , Proteínas de Soja , Animais , Antígenos de Plantas/química , Aspirina/efeitos adversos , Digestão , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Globulinas/química , Muco/química , Técnicas de Microbalança de Cristal de Quartzo , Proteínas de Armazenamento de Sementes/química , Proteínas de Soja/química , Soja/química
8.
Sci Rep ; 12(1): 12226, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35851408

RESUMO

Eosinophilic esophagitis (EoE) is a chronic inflammatory condition of the esophagus characterized by increased number of eosinophils. Currently, EoE diagnosis is based on endoscopic procedures for histopathological examination, eosinophils' counting and, often, in clinical practice, the challenge is the differentiation between EoE and gastroesophageal reflux disease (GERD). Our aim was to develop novel peptide ligand to Eosinophil cationic protein (ECP) present in EoE biopsies of patients with potential to be used for detection. We performed a comparative proteomic analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) of esophageal biopsies from pediatric patients with eosinophilic esophagitis, gastroesophageal reflux disease and control individuals. Then, phage display technology was used to select peptides against specific up-regulated protein from EoE patients. Twelve phage clones were selected after three biopanning rounds, and the best phage clone reactivity was evaluated by phage-ELISA assay using esophageal mucus samples from 94 pediatric patients. Mass spectrometry showed that eosinophil cationic protein (ECP) was one of the most up-regulated proteins in EoE patients, which is an eosinophil granule protein usually deposited on tissues to mediate remodeling, but in excess may cause fibrosis and hypertrophy, especially in allergic responses. A highly reactive ECP-ligand peptide (E5) was able to distinguish reactive mucus of EoE patients from GERD and the control individuals by Phage-ELISA, achieving a sensitivity of 84.62%, and a specificity of 82.72%. This is the first study that successfully demonstrated an antibody-like peptide targeting ECP at the esophagus mucus as a useful auxilliary tool for EoE diagnosis with a significant association with atopic disorders and dysphagia.ClinicalTrials.gov no.: NCT03069573.


Assuntos
Esofagite Eosinofílica , Refluxo Gastroesofágico , Criança , Cromatografia Líquida , Enterite , Proteína Catiônica de Eosinófilo , Eosinofilia , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/patologia , Eosinófilos/metabolismo , Gastrite , Refluxo Gastroesofágico/complicações , Humanos , Ligantes , Muco/metabolismo , Peptídeos , Proteômica , Espectrometria de Massas em Tandem
9.
Immunohorizons ; 6(7): 432-446, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35817532

RESUMO

The type 2 cytokines IL-4 and IL-13, which share use of an IL-4 receptor α-chain and its nuclear induction of the transcription factor STAT6, are crucial in elicitation and maintenance of allergic conditions including asthma. STAT6 binds poly(ADP-ribose) polymerase (PARP)14, an ADP-ribosyl monotransferase. Elimination of PARP14 by gene targeting led to attenuation of OVA-specific allergic lung inflammation. However, PARP14 has multiple functional domains apart from the portion that catalyzes ADP-ribosylation, and it is not clear whether inhibition of the catalytic function has any biological consequence. Using BALB/c mice sensitized to the allergen Alternaria alternata, we show that peroral administration of RBN012759, a highly selective inhibitor of ADP-ribosylation by PARP14 with negligible impact on other members of the PARP gene family, achieved biologically active plasma concentrations and altered several responses to the Ag. Specifically, the pharmaceutical compound decreased mucus after allergen challenge, blunted the induced increases in circulating IgE, and prevented suppression of IgG2a. We conclude that PARP14 catalytic activity can contribute to pathogenesis in allergic or atopic processes and propose that other biological endpoints dependent on ADP-ribosylation by PARP14 can be targeted using selective inhibition.


Assuntos
Alérgenos , Asma , Animais , Asma/tratamento farmacológico , Modelos Animais de Doenças , Imunoglobulina E , Camundongos , Muco/metabolismo , Preparações Farmacêuticas/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/uso terapêutico
10.
Front Immunol ; 13: 895100, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35874776

RESUMO

Pulmonary diseases represent four out of ten most common causes for worldwide mortality. Thus, pulmonary infections with subsequent inflammatory responses represent a major public health concern. The pulmonary barrier is a vulnerable entry site for several stress factors, including pathogens such as viruses, and bacteria, but also environmental factors e.g. toxins, air pollutants, as well as allergens. These pathogens or pathogen-associated molecular pattern and inflammatory agents e.g. damage-associated molecular pattern cause significant disturbances in the pulmonary barrier. The physiological and biological functions, as well as the architecture and homeostatic maintenance of the pulmonary barrier are highly complex. The airway epithelium, denoting the first pulmonary barrier, encompasses cells releasing a plethora of chemokines and cytokines, and is further covered with a mucus layer containing antimicrobial peptides, which are responsible for the pathogen clearance. Submucosal antigen-presenting cells and neutrophilic granulocytes are also involved in the defense mechanisms and counterregulation of pulmonary infections, and thus may directly affect the pulmonary barrier function. The detailed understanding of the pulmonary barrier including its architecture and functions is crucial for the diagnosis, prognosis, and therapeutic treatment strategies of pulmonary diseases. Thus, considering multiple side effects and limited efficacy of current therapeutic treatment strategies in patients with inflammatory diseases make experimental in vitro and in vivo models necessary to improving clinical therapy options. This review describes existing models for studyying the pulmonary barrier function under acute inflammatory conditions, which are meant to improve the translational approaches for outcome predictions, patient monitoring, and treatment decision-making.


Assuntos
Pulmão , Pneumonia , Poluentes Atmosféricos , Células Apresentadoras de Antígenos/imunologia , Peptídeos Antimicrobianos , Quimiocinas , Citocinas , Granulócitos/imunologia , Humanos , Pulmão/imunologia , Muco/imunologia
11.
Zhongguo Zhong Yao Za Zhi ; 47(13): 3475-3480, 2022 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-35850798

RESUMO

The present study prepared shell-core nanoparticles comprising poly(lactic-co-glycolic acid)(PLGA) cores encapsulated by shells composed of mixed lipids(Lipoid S100 and DSPE-PEG 2000) or polymer F127 to investigate the effects of shell composition on overcoming physiological barriers of gastrointestinal mucus and intestinal epithelial cells and improving bioavailability.The results are expected to provide references for the research on the improvement of the oral bioavailability of Chinese medicine by nanocar-riers. Silibinin(SLB) was used as a model drug to prepare PLGA nanoparticles coated with the shell of mixed lipids(SLB-LPNs) or F127(SLB-FPNs) via a modified nanoprecipitation method.Transmission electron microscopy showed that both LPNs and FPNs were spherical with a core-shell structure.The average particle sizes of SLB-LPNs and SLB-FPNs were(94.13±2.23) and(95.42±4.91) nm, respectively.The Zeta potential values were(-39.3±2.8) and(-17.0±0.2) mV, respectively.X-ray diffraction analysis revealed the presence of SLB in the two types of nanoparticles in a molecular or amorphous state.The ability of nanoparticles to cross both the mucus and epithelial barriers were evaluated using the cellular internalization kinetics assay.LPNs showed a higher rate of cell internalization than FPNs, indicating that LPNs could penetrate the mucus layer and become internalized by cells more rapidly.As revealed by the in vivo pharmacokinetic assay in rats with SLB suspension as the reference, the relative oral bioavailability of SLB-LPNs and SLB-FPNs was 400.37% and 923.31%, respectively.The effect of SLB-FPNs in improving oral bioavailability was more significant than that of SLB-LPNs.In summary, shell composition can influence the ability of nanoparticles to overcome oral physiological bar-riers, such as the mucus layer and intestinal epithelial cells, and improve oral bioavailability.Shell-core structured nanoparticles are promising nanocarriers for oral drug delivery systems.


Assuntos
Nanopartículas , Animais , Disponibilidade Biológica , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Muco , Nanopartículas/química , Tamanho da Partícula , Polímeros , Ratos
12.
Zhongguo Zhong Yao Za Zhi ; 47(14): 3898-3907, 2022 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-35850848

RESUMO

This study observed the pharmacological effects of Feilike Mixture(FLKM) in stopping cough, eliminating phlegm, and relieving asthma through animal experiments, and explored its mechanism using network pharmacology. The antitussive effect was detected by citric acid-induced guinea pig cough model, the expectorant effect by mouse phenol red excretion experiment and lipopolysaccharide-induced mucus hypersecretion rat model, and the antiasthmatic effect by histamine phosphate-induced guinea pig asthma model. The chemical components of FLKM were collected by TCMSP, TCMID, TCMIP, and BATMAN-TCM databases and literature search, and the potential active components were screened through ADMETlab 2.0. The targets of FLKM were obtained by STITCH, SwissTargetPrediction, and TCMSP, and the symptom targets of cough, phlegm, and asthma were acquired through SymMap database. After taking the intersection of FLKM targets and symptom targets, this study used the OECloud tool to perform Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. RESULTS:: demonstrated that FLKM 0.43-1.74 g·kg~(-1) reduced the number of coughs in guinea pigs within 3 min(P<0.05, P<0.01), and FLKM 6-12 g·kg~(-1) increased the tracheal phenol red excretion in mice(P<0.01). Moreover, FLKM 2-8 g·kg~(-1) inhibited the number of goblet cells(P<0.05, P<0.01), and FLKM 7-11.2 g·kg~(-1) prolonged the incubation period of asthma(P<0.05). A total of 115 potential active components and 910 targets of FLKM were obtained through network pharmacological analysis. FLKM had 27, 12, and 7 targets for stopping cough, eliminating phlegm, and relieving asthma, respectively. The GO and KEGG enrichment analysis found that there were commonalities and characteristics, among which cytokine-cytokine receptor interaction and infectious disease-related signaling pathway were shared. FLKM has a good effect of stopping cough, eliminating phlegm, and relieving asthma through animal experiments and network pharmacology.


Assuntos
Experimentação Animal , Asma , Medicamentos de Ervas Chinesas , Animais , Asma/induzido quimicamente , Asma/tratamento farmacológico , Tosse/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Cobaias , Camundongos , Muco , Farmacologia em Rede , Fenolsulfonaftaleína , Ratos
13.
14.
J Agric Food Chem ; 70(30): 9536-9546, 2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35852590

RESUMO

High consumption of polyphenol-rich green tea, coffee, fruits, and vegetables is associated with a low risk of human chronic diseases. Recent studies highlight the relevance of polyphenol-mediated gut microbiota modulation and its impact on mucus barrier. Herein, we study the direct interaction of epicatechin (EC), epigallocatechin gallate (EGCG), and tannic acid (TA) with intestinal mucin by isothermal titration calorimetry and multiple particle tracking and the impact on mucus barrier using ex vivo mucus and Caco-2/HT29-MTX cocultures. Results show that pyrogallol-containing polyphenols EGCG and TA exhibit strong binding to intestinal mucin and reinforce mucus barrier, whereas EC does not. ECGG and TA also mitigate gliadin-mediated cytotoxicity and inflammation. The chemical binding of EGCG and TA to the nucleophilic thiol groups of mucins shows their roles as cross-linkers of mucin networks. These results bring a novel understanding of the health benefits of polyphenols and provide support for the consumption of pyrogallol-containing beverages like green tea as a potential dietary therapy for gluten-related disorders.


Assuntos
Catequina , Polifenóis , Células CACO-2 , Catequina/química , Humanos , Mucinas/química , Muco/metabolismo , Polifenóis/química , Polifenóis/farmacologia , Pirogalol , Chá/química
15.
Biomed Pharmacother ; 152: 113244, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35687911

RESUMO

Airway mucus hypersecretion is a vital pathophysiologic feature in chronic obstructive pulmonary disease (COPD) patients in which airflow limitation result, and it is key to strategizing in the management of COPD. To investigate the mechanisms underlying the action of interleukin-6 neutralizing antibody (IL-6 Ab) in attenuating airway mucus hypersecretion in COPD, human and mouse primary bronchial epithelial cells from COPD patients and mice were isolated, human organoid model of trachea was established and all treated with IL-6 and/or IL-6 Ab. The differential expression of Muc5ac and Nrf2 were determined in pDHBE compared to pNHBE cells via high-throughput sequencing of transcriptome. The serum concentration of Muc5ac was significantly elevated and positively correlated with IL-6 in COPD patients using ELISA, and the excessive mucus secretion was observed in the trachea of COPD patients using HE, AB-PAS and IHC staining. The levels of Muc5ac were significantly elevated in the IL-6-treated group, and diminished with IL-6 Ab treatment, both in vitro and in the organoid model using qRT-PCR, WB and IF. The expression levels of protein Muc5ac were significantly reduced in cells transfected with the IL-6 small interfering RNA (siRNA-IL-6), which was in contrast to the levels of protein Nrf2, and the protective effects of IL-6 Ab were inhibited in cells transfected with Nrf2 short hairpin RNA (shRNA-Nrf2). IL-6 Ab significantly attenuated hypersecretion of airway mucus by inducing nuclear translocation of Nrf2 in COPD. These findings indicated that IL-6 Ab may constitute a novel therapeutic agent for IL-6-induced airway mucus hypersecretion by improving airflow limitation in COPD patients.


Assuntos
Interleucina-6 , Doença Pulmonar Obstrutiva Crônica , Animais , Anticorpos Neutralizantes/uso terapêutico , Humanos , Interleucina-6/metabolismo , Camundongos , Mucina-5AC/genética , Mucina-5AC/metabolismo , Muco/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico
16.
J Ethnopharmacol ; 295: 115449, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-35688257

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Pinelliae Rhizoma Praeparatum (PRP) is a traditional processed product of Pinellia ternata (Thunb.) Berit., which mainly used for treating cold asthma (CA). However, the mechanism of action of PRP for treating CA have not been fully elucidated. AIM OF THE STUDY: To investigate the core active constituents and the pharmacological mechanism of PRP against CA. MATERIALS AND METHODS: Ovalbumin (OVA) and cold water-induced cold asthma model were established in male mice. The effects of water extract from PRP were evaluated by general morphological observation, expectorant activity, airway hyperresponsiveness, mucus hypersecretion, inflammatory cytokines, etc. Additionally, the mRNA and protein expression of mucin 5AC (MUC5AC) and aquaporin 5 (AQP5) in vivo and in vitro were detected by immunohistochemistry (IHC), qRT-PCR, and western blotting. The mechanisms of action were investigated through network pharmacology and transcriptomic, and validated through western blotting and molecular docking. RESULTS: PRP exhibited a favorable expectorant activity, and significantly reduced the airway inflammation, mucus secretion, and hyperresponsiveness in cold asthma model. It also reduced the levels of IL-4, IL-5, IL-8, and IL-13 in bronchoalveolar lavage fluid (BALF) and IL-4 and total IgE in serum, while obviously increased the levels of IL-10 and IFN-γ in serum for asthmatic mice. Meanwhile, PRP also attenuated the pathological changes and mucus production in cold asthmatic mice. Moreover, the downregulation of MUC5AC and upregulation of AQP 5 were detected by western blotting and qRT-PCR after administration with PRP both in vivo and in vitro. PRP expectedly inhibited the protein expression of PKC-α, SRC, p-EGFR, p-ERK1/2, p-JNK, p-p38, p-PI3K, and p-Akt levels in vivo. CONCLUSIONS: These combined data showed that PRP suppressed the allergic airway inflammation of CA by regulating the balance of Th1 and Th2 cytokines and the possible involvement of the PKC/EGFR/MAPK/PI3K-Akt signaling pathway. Pentadecanoic acid, licochalcone A, ß-sitosterol, etc. were considered as main active ingredients of PRP against CA. This study provides a novel perspective of the classical herbal processed product PRP in the treatment of CA.


Assuntos
Asma , Pinellia , Animais , Asma/patologia , Líquido da Lavagem Broncoalveolar/química , Citocinas/metabolismo , Receptores ErbB/metabolismo , Expectorantes/uso terapêutico , Inflamação/metabolismo , Interleucina-4/metabolismo , Pulmão , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Muco/metabolismo , Ovalbumina/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Pinellia/química , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais , Água/farmacologia
17.
Sci Adv ; 8(26): eabn3917, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35767627

RESUMO

Oral drug delivery systems have great potential to treat colorectal cancer (CRC). However, the drug delivery efficiency is restricted by limited CRC-related intestine positioning and dense mucus barrier. Here, we present a biological chemotaxis-guided self-thermophoretic nanoplatform that facilitates precise intestinal positioning and autonomous mucus penetration. The nanoplatform introduces asymmetric platinum-sprayed mesoporous silica to achieve autonomous movement in intestinal mucus. Furthermore, inspired by the intense interaction between pathogenic microbes and CRC, the nanoplatform is camouflaged by Staphylococcus aureus membrane to precisely anchor in CRC-related intestine. Owing to 4.3-fold higher biological chemotactic anchoring of CRC-related intestine and 14.6-fold higher autonomous mucus penetration performance, the nanoplatform vastly improves the oral bioavailability of cisplatin, leading to a tumor inhibition rate of 99.1% on orthotopic CRC-bearing mice. Together, the exquisitely designed nanoplatform to overcome multiple physiological barriers provides a new horizon for the development of oral drug delivery systems.


Assuntos
Neoplasias Colorretais , Nanopartículas , Animais , Quimiotaxia , Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Camundongos , Muco , Dióxido de Silício
18.
Proc Natl Acad Sci U S A ; 119(27): e2116197119, 2022 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-35767643

RESUMO

The majority of viruses within the gut are obligate bacterial viruses known as bacteriophages (phages). Their bacteriotropism underscores the study of phage ecology in the gut, where they modulate and coevolve with gut bacterial communities. Traditionally, these ecological and evolutionary questions were investigated empirically via in vitro experimental evolution and, more recently, in vivo models were adopted to account for physiologically relevant conditions of the gut. Here, we probed beyond conventional phage-bacteria coevolution to investigate potential tripartite evolutionary interactions between phages, their bacterial hosts, and the mammalian gut mucosa. To capture the role of the mammalian gut, we recapitulated a life-like gut mucosal layer using in vitro lab-on-a-chip devices (to wit, the gut-on-a-chip) and showed that the mucosal environment supports stable phage-bacteria coexistence. Next, we experimentally coevolved lytic phage populations within the gut-on-a-chip devices alongside their bacterial hosts. We found that while phages adapt to the mucosal environment via de novo mutations, genetic recombination was the key evolutionary force in driving mutational fitness. A single mutation in the phage capsid protein Hoc-known to facilitate phage adherence to mucus-caused altered phage binding to fucosylated mucin glycans. We demonstrated that the altered glycan-binding phenotype provided the evolved mutant phage a competitive fitness advantage over its ancestral wild-type phage in the gut-on-a-chip mucosal environment. Collectively, our findings revealed that phages-in addition to their evolutionary relationship with bacteria-are able to evolve in response to a mammalian-derived mucosal environment.


Assuntos
Bactérias , Bacteriófagos , Trato Gastrointestinal , Membrana Mucosa , Animais , Bactérias/virologia , Bacteriófagos/genética , Bacteriófagos/fisiologia , Proteínas do Capsídeo/genética , Trato Gastrointestinal/virologia , Membrana Mucosa/virologia , Muco , Mutação , Simbiose
19.
AAPS PharmSciTech ; 23(6): 179, 2022 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-35761150

RESUMO

The rectal enemas of berberine hydrochloride (BH) have emerged as one of the most effective strategies in the clinical treatment of ulcerative colitis (UC). However, oral dosages of BH exhibit a poor anti-inflammatory effect of UC, which may attribute to premature absorption of BH by the upper gastrointestinal tract. Moreover, the thick colonic mucus layer obstructs the penetration of the drug, resulting in low bioavailability to the inflammatory site of the colon. The aim of this study was to develop the mucus-penetrating sodium alginate-chitosan nanoparticles (SA-CS NPs) for oral delivery of BH to the site of colonic ulcer lesions. BH-loaded SA-CS NPs were developed through the ionic gelation method and analyzed for physicochemical characteristics, release performance, penetrability, site retention, and therapeutic efficacy. The results showed that the NPs have a particle size of 257 nm with a negative charge, presenting desired pH-dependent release behavior. The permeation studies elucidated that negatively charged SA-CS NPs had 2.9 times higher mucus penetration ability than positively charged CS NPs. An ex vivo retention study indicated the high retention of BH-SA-CS NPs at the colon site for more than 16 h. In vivo therapeutic effectiveness demonstrated that the prepared NPs could not only alleviate colonic injury by decreasing the disease activity index and colon mucosa damage index, but also improve the immunologic function by decreasing the spleen index. In conclusion, the BH-SA-CS NPs could enhance the mucus permeability and deliver drugs to the colonic inflammation site, providing new insights into improving the therapeutic effect of UC.


Assuntos
Berberina , Quitosana , Colite Ulcerativa , Nanopartículas , Administração Oral , Alginatos , Colite Ulcerativa/tratamento farmacológico , Portadores de Fármacos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Humanos , Inflamação/tratamento farmacológico , Muco
20.
J Colloid Interface Sci ; 624: 307-319, 2022 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-35660900

RESUMO

The aim of this study was to improve the bioavailability of polymyxin B (PMB) in pulmonary nebulized drug delivery. To this end, we developed a nano-delivery system that penetrates the mucus barrier of the lung. Hydrophilic hyaluronic acid (HA) was combined with a water-in-oil system containing a poly (lactic acid)-glycolic acid copolymer of PMB to prepare HA@PLGA-PMB nanoparticles (NPs) with good surface properties. HA@PLGA-PMB NPs with suitable electrical properties, particle size, and good hydrophilicity prevented strong interactions between the NPs and mucus, thereby allowing more drugs to enter deeper into the lung. Compared to the free drug PMB, NPs had more than 2-fold higher mucus penetration efficiency in vitro and better delivery to infected alveolar cells during in vivo nebulization. NPs had better biocompatibility, which further reduced the drug toxicity. More importantly, NPs showed better antimicrobial therapeutic efficacy in the treatment of lung infections in mice. These findings may provide support for the clinical application of nebulized pulmonary antibiotics.


Assuntos
Ácido Hialurônico , Nanopartículas , Animais , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Glicolatos , Ácido Láctico , Pulmão , Camundongos , Muco , Tamanho da Partícula , Ácido Poliglicólico , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Polimixina B/farmacologia
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